APPLICANT'S DESCRIPTION (provided by Applicant) The overall goal of the program project is to design and synthesize new drugs for the treatment of cancer. The goal of this "Mechanism of action of nucleoside analogs" is to perform experiments to characterize the biochemical pharmacology of the new compounds that will be synthesized in projects 2 and 4. The information that will be gained about the mechanism of action of these compounds is vital to the rational development of these compounds as anticancer agents. In addition, this information will be provided to the organic chemists in projects 2 and 4 during regular group meetings to be used in the rational design of new agents. This project has 3 specific aims. In the first aim we will evaluate all compounds for toxicity to CEM cells to identify active and inactive agents. In the second aim we will perform biochemical experiments on selected compounds to gain a preliminary understanding of their mechanism of action. In the third aim, we will perform extensive studies on compounds that warrant a more thorough evaluation. Studies are planned to characterize in detail the mechanism of action of 2 agents that have demonstrated excellent in vivo antitumor activity, 4'-thio-arabinofuranosylcytosine and 2-Cl-2'-F-2'-deoxy- arabinofuranosyladenine (Clofarabine). These studies should lead to a comprehensive understanding of the mechanism of action of new agents that will aid in their development by determining how these compounds differ form existing anticancer drugs.